COMBINED ANALYSIS OF ISLET-CELL ANTIBODIES WHICH CROSS-REACT WITH MOUSE PANCREAS, ANTIBODIES TO THE M(R) 64,000 ISLET PROTEIN, AND ANTIBODIES TO GLUTAMATE-DECARBOXYLASE IN SUBJECTS AT RISK FOR IDDM

With regard to progression to diabetes, ICA cross-reactive with mouse pancreas, antibodies to the M, 64,000 islet antigen (64K), antibodies immunotrapping brain GAD activity, and IAA were analysed in 53 ICA-positive first-degree relatives of IDDM patients and 18 ICA-positive schoolchildren without a family history of diabetes. Sera from 29 (55%) relatives did not bind to mouse pancreas, whereas 24 (45%) displayed cross-species reaction. ICA titres on human and mouse pancreas were weakly correlated in the overall population (p < 0.05) but more strongly (p < 0.01) in only those subjects who displayed antibodies on tissues from both species. CAD and 64K antibodies were detected in 31% and 35% of relatives. In schoolchildren, the frequencies of cross-species reactive ICA (22%), GAD antibodies (6%), 64K antibodies (22%), and IAA (6%), were lower (p < 0.05) than in relatives. A strong correlation (p < 0.0001) was observed between GAD and 64K antibodies. GAD or 64K antibodies were strongly correlated with ICA on human pancreas (p < 0.0001) but poorly with ICA on mouse pancreas (p = 0.05). After pre-incubation of sera with brain homogenate, ICA titres were unaffected on mouse pancreas but reduced on human pancreas. ICA-positive subjects who displayed neither cross-species reactive ICA nor GAD or 64K antibodies were more frequent (p < 0.05) among schoolchildren than relatives, whereas subjects who displayed all antibody specificities were more numerous (p < 0.04) in relatives. All relatives with ICA binding only to human pancreas, as well as all schoolchildren, permanently displayed an AIRG higher than the first control percentile and remained non-diabetic. Five of ten relatives with cross-species reactive ICA, GAD and 64K antibodies at the same time displayed acute insulin response to glucose which fell below the first control percentile and developed the disease. The cross-species heterogeneity of ICA was thus confirmed in a large series of relatives and revealed in the general population. Detection of cross-species reactive ICA, GAD antibodies, or 64K antibodies enhances the prognostic significance after conventional ICA screening. The combination of these antibodies is more indicative of diabetes development than any antibody alone. Correlations between tests and absorption experiments indicate that GAD 64 is an ICA antigen on human but not on mouse pancreas, and that ICA which recognize GAD 64K coexist with others which react with mouse pancreas but not with CAD. A third ICA subset might have been revealed by high-titred ICA without either cross-species reactivity or CAD or 64K antibodies. This latter state was more frequent in the general population than in relatives and might typify an early immune response which may or may not progress.